Spinal Muscular Atrophy Syndrome

Second most common lethal recessive disease in the white population. Neurological disorder (five types) that leads to severe amyotrophy with respiratory insufficiency has been described. Clinical evolution according to the type involved.

• Spinal Muscular Atrophy Type I (Werdnig-Hoffman Disease; SMA Infantile Acute form; Infantile SMA)
• Spinal Muscular Atrophy Type II (Dubowitz Disease; Intermediate type of SMA; Infantile Chronic form of SMA)
• Spinal Muscular Atrophy Type III (Juvenile Muscular Atrophy; Childhood-Onset Proximal SMA; Kugelberg Welander Syndrome; Childhood Isolated SMA; Wohlfart-Kugelberg-Welander Syndrome)
• Spinal Muscular Atrophy Type IV (Distal Hereditary Motor Neuropathy; Adult Spinal Muscular Atrophy)
• Spinal Muscular Atrophy Type V or Adult Onset X-Linked SMA (Kennedy Disease; Bulbospinal Muscular Atrophy)

1:6000 live births.

Autosomal recessive. However, some forms have been suggested to be inherited as autosomal dominant and occasionally X-linked. In adult onset (type IV), the causal gene is located on chromosome 12 (12q24).

The disorder is characterized by degeneration and loss of anterior horn cells in the spinal cord and sometimes also in the brainstem, leading to symmetrical muscle weakness and wasting of voluntary muscles. There is evidence that at least two identifiable genes are associated with the disease: SMN1 (survival motor neurone) and NAIP (neuronal apoptosis inhibitory protein), and possibly a third gene, BTF2p44 (basal transcription factor 2H, subunit p44). The SMN gene is missing in the majority of SMA patients and small, intragenic mutations have also been associated with SMA. Approximately half of the severely affected patients are also missing the NAIP gene, which may affect the severity of the disease.

Clinical features. CT scan and MRI are used to exclude other pathologies. Electromyography usually shows neurogenic and occasional myogenic pattern. Nerve conduction study is normal. Serum creatine kinase is normal. Muscle biopsy shows a large number of round atrophic fibers and clumps of hypertrophic fibers that are type I by ATPase reaction. DNA testing for SMN and NAIP genes is reliable and confirmatory for the phenotype. Prenatal DNA testing is less reliable because a small percentage of population lack an SMN gene but are not clinically affected.

Spinal Muscular Atrophy is the second most common lethal autosomal recessive disease in the white population.

Type I (Werdnig-Hoffman Disease): Early onset and diagnosis (before 3 months), with severe intrauterine growth retardation, polyhydramnios, and tongue fasciculations. Child never sits or walks. There is difficulty with swallowing and feeding. Respiratory function is always severely impaired: diaphragmatic breathing, respiratory infection, and distress. Absent deep tendon reflexes, hypotonia, and weakness, but normal intelligence and no sensory loss are observed. Restricted joint mobility and kyphoscoliosis are also frequent. Death before age of 2 years old is common but does not always occur.

Type II (Dubowitz Disease or Chronic form): Intermediate SMA with onset between the age of 3 and 18 months and survival beyond 4 years (usually until adolescence or later). Child often can sit unsupported but never ambulates. Feeding problems, recurrent pulmonary aspiration and pneumonia, and tongue fasciculations occur less often than in type I, but a fine tremor in the outstretched fingers is common.

Type III (Wohlfart-Kugelberg-Welander Disease; Childhood-Onset Proximal SMA): This is a mild, chronic form with onset after the age of 18 months. Typical presentation includes atrophy and weakness of the proximal limb muscles, primarily in the legs, followed by distal involvement. Neurological testing shows hypotonia, decreased or absent deep tendon reflex, muscle fasciculation, and no sensory loss. However, tongue fasciculations are rarely seen. Joint deformities occur secondary to muscle weakness, often with abducted hips and flexed knees. Progressive loss of pulmonary reserve with frequent pulmonary infections is common and respiratory failure is usually the common mode of death. Presentation after 18 months of age. Individuals develop ability to stand and walk but with abnormal gait. Intracardiac arrhythmia can be observed and may require a pacemaker.

Type IV (Adult Onset): Beginning between the end of the fourth and the sixth decades and showing rapid progression without evidence of cortical spinal tract dysfunction. Death from respiratory failure occurs within 2 years of onset.

Type V or Adult-Onset X-Linked SMA (Kennedy Syndrome; Bulbospinal Muscular Atrophy): Occurs only in men, although 50% of female offspring are carriers. This form of SMA is associated with a mutation in the gene that codes for part of the androgen receptor; male presents with gynecomastia. Tongue and facial muscles movement are present.

Other variant types of SMA have also been described, including the Facioscapulohumeral type and the Ryukyuan type.

Evaluate the extent of the muscle weakness (clinical, EMG); impact on the respiratory function (clinical, chest radiograph, respiratory function test, arterial blood gas analysis); cardiac function for SMA type III (ECG, Holter, echocardiography); and malnutrition (clinical, albumin). Check blood electrolytes, particularly serum potassium and creatine kinase.

Respiratory failure is the main concern in these patients because it is the most common complication and eventual cause of death. Elective surgery under general anesthesia is not indicated if respiratory function is severely reduced (usually forced vital capacity [FVC] <25%, peak expiratory flow rate [PEFR] <30%). Elective intensive care unit admission and mechanical support after general anesthesia should be considered for major procedure and/or for patient with poor respiratory reserve. Bulbar involvement is rare with this disorder but represents a potential cause for pulmonary aspiration if present. Hyperkalemia may occur prior to anesthesia as a consequence of continuing muscle wasting and is likely to rise to a dangerous level with the use of suxamethonium. Central neural blockade for peripheral surgery is not advisable in most cases because it may worsen the clinical picture of the disease. It is unclear if epidural analgesia may improve the respiratory function and facilitate earlier extubation. No clear evidence of an association with malignant hyperthermia. Joint deformities may cause difficulty in obtaining intravenous access and positioning of patient.

There is no evidence of an increase risk of malignant hyperthermia (neurological disorder), however, it seems prudent to avoid succinylcholine because of contractures and bone fragility (risk of hyperkalemia and fractures). Non-depolarizing muscle relaxants can be used but require adequate titration and monitoring. The use of opioid agents is not contraindicated however, when indicated, regional anesthesia should be preferred because of the decrease risk of respiratory depression. Remifentanil can be useful because of its short duration.

Myopathy, Distal, Welander Type: Gene located on 2p13. Onset in the fourth decade with muscle weakness, wasting of the small muscles of the hands, myotonia, and sensory changes.

Aran-Duchenne SMA (Cruveilhier Disease; Duchenne-Aran SMA; Duchenne-Aran Syndrome; Duchenne-Griesinger Disease): Muscular fasciculation, simian hand (eventually becoming “cadaveric hand”), round-shouldered posture, and forward drop of the head, drop foot, steppage gait, and dyspnea.

SMA Congenital Nonprogressive of Lower Limbs: Characterized by nonprogressive muscular atrophy involving mainly the lower extremities. Onset is in infancy or early childhood. The clinical features include atrophy of the muscles of the lower extremity, mild flexion contractures of the knees, pes equinovarus, and mild weakness of the adductor muscles. There may also be minimal involvement of the jaw muscles and neck flexors, however, it is not considered characteristic of this medical condition. Sensory examination and tendon reflexes are normal. Serum creatine kinase activity may be marginally elevated. This disorder differs from arthrogryposis multiplex congenita because there is usually no involvement of the upper extremities. It differs from other spinal muscular atrophies because it appears early in life and is nonprogressive. Scapuloperoneal SMA is characterized by stridorous breathing in the newborn due to laryngeal palsy, while the presence of progressive lower limb weakness, and contractures appear only in the first or second decade. Autosomal dominant inheritance has been suggested.

Proximal SMA Adult Type (Finkel Late Adult Type Spinoceerebellar Atrophy Syndrome): Characterized by an onset age in the fourth decade (median age of 37 years). It has been estimated that 30% of adult onset cases of SMA are due to an autosomal dominant gene. It has also been suggested that a separate gene may be responsible for the autosomal dominant SMA observed in childhood (birth to 8 years). The clinical features include a slow and progressive spinal muscular atrophy of late onset, which is defined as a slow loss of muscle strength and progressive proximal muscular atrophy. It usually begins in the legs and later involves the arms and is associated with hypoactive or absent deep tendon reflexes and generalized fasciculations.

X-Linked Lethal Infantile SMA: This congenital form of spinal muscular atrophy is characterized by severe hypotonia, multiple joint contractures, generalized osteopenia, and congenital fractures. The diagnosis is usually confirmed by sural nerve and muscle biopsies consistent with spinal muscular atrophy. Other clinical features may include respiratory difficulty, decreased muscle mass, congenital fractures, and severe osteopenia. Contractures are usually not present.